Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression

Key Points Acute effects impact the clinical endpoint independently of treatment effects on the chronic slope. Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials. Background Slope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs). Methods We estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. Results Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R 2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m 2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%–15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years. Conclusions Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

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Publication Details

Journal
Clinical Journal of the American Society of Nephrology
Published
2025-04-15
DOI
https://doi.org/10.2215/cjn.0000000662
Citations
3
Primary Topic
Chronic Kidney Disease and Diabetes
Type
article
Field-Weighted Citation Impact
4.29
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article

Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression

Lucia Del Vecchio, Philip Kam‐Tao Li, Robert D. Toto, Thierry Hannedouche et al.
3 citations
Clinical Journal of the American Society of Nephrology
Chronic Kidney Disease and Diabetes
4.29
article

Clinical Implications of Slope of GFR in Clinical Trials of CKD Progression

Lucia Del Vecchio, Philip Kam‐Tao Li, Robert D. Toto, Thierry Hannedouche, Willem Collier, Brendon Lange Neuen, Hiddo J.L. Heerspink, Christoph Wanner, Mark Woodward, Fernando Caravaca‐Fontán, Benjamin Haaland, Lesley A. Inker, Julia B. Lewis, Francesco Locatelli, Sunil V. Badve, Enyu Imai, Bart Maes, Ronald D. Perrone, Tazeen H. Jafar, Francesco Paolo Schena, Chong Zhang, Arjan D. van Zuilen, Tom Greene, Jürgen Floege
article en
3 citations

Abstract

Key Points Acute effects impact the clinical endpoint independently of treatment effects on the chronic slope. Our findings support the 3-year total slope as the primary slope-based outcome in randomized trials. Background Slope of the GFR is considered a validated surrogate endpoint for CKD trials. However, differing short-term and long-term treatment effects on GFR slope can create ambiguities concerning the appropriate period for evaluating slope, in part because current methods cannot separate the distinct contributions of the acute (before 3 months) and chronic (after 3 months) slopes for treatment effects on clinical endpoints (CEs). Methods We estimated treatment effects on the acute and chronic GFR slopes and on the established CE of kidney failure or serum creatinine doubling for 66 randomized treatment comparisons from previous CKD clinical trials. We used a novel Bayesian meta-regression framework to relate treatment effects on the established CE to both the acute and chronic slopes in a single multivariable model to determine the independent contributions of the acute and chronic slopes. Results Treatment effects on both the acute and chronic slopes independently predicted the treatment effect on the established CE with a high median R 2 (95% credible interval) of 0.95 (0.79 to 1.00). For a fixed treatment effect on the chronic slope, each 1 ml/min per 1.73 m 2 greater acute GFR decline for the treatment versus control increased the hazard ratio for the established CE by 11.4% (7.9%–15.0%), against the treatment. The optimal weights for the acute and chronic slopes were consistent with the 3-year total slope defined as the average slope extending from baseline to 3 years. Conclusions Treatment effects on both the acute and chronic GFR slopes are independent determinants of the effects on the established CE, with variation in acute effects accounting for much of the observed variation in treatment effects on the CE across previous trials. Our results establish that acute effects affect the CE independently of treatment effects on the chronic slope and support the 3-year total slope as the primary slope-based outcome in randomized trials.

Clinical Journal of the American Society of NephrologyVol. 20(5)
University of Southern California (US), Tufts Medical Center (US), University Medical Center Groningen (NL), University of Groningen (NL), Chinese University of Hong Kong (HK), The George Institute for Global Health (GB), University of Utah (US), University of Würzburg (DE), University Medical Center Utrecht (NL), UNSW Sydney (AU), EM Strasbourg Business School (FR), Research Institute Hospital 12 de Octubre (ES), Southwestern Medical Center (US), Comprehensive Cancer Center Mainfranken (DE), The George Institute for Global Health (AU), Takara (Japan) (JP), Alessandro Manzoni Hospital (IT), Prince of Wales Hospital (CN), Universitätsklinikum Würzburg (DE), Duke-NUS Medical School (SG), Azienda Socio Sanitaria Territoriale Lariana (IT), AZ Delta (BE), Ospedale Sant'Anna (IT), TetraLogic Pharmaceuticals (United States) (US), Southwestern Medical Center (US), Aziende Socio Sanitarie Territoriali di Lecco, Imperial College London (GB), University of Bari Aldo Moro (IT), Université de Strasbourg (FR), The University of Texas Southwestern Medical Center (US), RWTH Aachen University (DE), Vanderbilt University Medical Center (US)
Good health and well-being
Openalex Percentile: Top 6%
Chronic Kidney Disease and Diabetes
4.29
DOIOpen Access PDFOpenAlex
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